Fabre Louis F, Timmer Cees J
Fabre Research Clinic, Inc., Houston, Texas, and.
Department of Drug Metabolism and Kinetics, NV Organon, Oss, the Netherlands.
Curr Ther Res Clin Exp. 2003 Sep;64(8):580-98. doi: 10.1016/j.curtheres.2003.09.012.
The new antidepressant gepirone acts preferentially on 5-hydroxytryptamine type 1A (5-HT1A) receptors and functions as a 5-HT1A agonist. Placebo-controlled clinical studies have established that gepirone has a good safety profile and is effective for the treatment of depression. A previous study showed that administration of gepirone immediate release 15 minutes after a meal instead of during a fast increased the mean area under the plasma concentration-time curve (AUC) by 37%. Gepirone was reformulated into extended release (ER), which necessitated further exploration of the effects of food on bioavailability.
This article describes 2 studies of the pharmacokinetic properties of gepirone ER and 1 of its metabolites, 1(2-pyrimidinyl)-piperazine (1-PP), in healthy subjects. In study 1, we assessed the effects of food and the influence of time of food intake relative to dosing on the bioavailability of gepirone ER. The objective of study 2 was to confirm that gepirone ER has similar pharmacokinetic characteristics under fed and fasting conditions.
Two open-label, randomized, single-dose, crossover studies balanced for first-order residual effects were conducted to assess the bioavailability of gepirone from ER tablets. Healthy male subjects received a 20-mg oral dose of gepirone ER. In study 1, subjects took the gepirone ER dose after a 10-hour overnight fast or 1 hour before, 15 minutes after, or 2 hours after a standard high-fat meal. In study 2, subjects either took the gepirone ER dose after a 10-hour overnight fast and continued to fast for 4 more hours or took the gepirone ER dose 15 minutes after a standard high-fat meal.
Twenty-eight men (mean [SD] age, 27.2 [6.6] years) participated in study 1, and 27 men (mean [SD] age, 31.8 [9.6] years) participated in study 2. In study 1, the mean (SD) maximum peak plasma concentration (Cmax) for gepirone ER was 69.2% higher (3.25 [1.71] vs 1.92 [0.96] ng/mL) (P≤0.05) and the AUC from time 0 to 30 hours for gepirone ER was 31.9% higher (39.3 [20.6] vs 29.8 [15.3] ng/mL·h) (P≤0.05) for the 15-minute postprandial dose than for the fasting dose, respectively. In study 2, the mean Cmax for gepirone was 62.0% higher (4.13 vs 2.55 ng/mL) and the mean AUC from time 0 to infinity for gepirone was 24% higher (38.71 vs 31.14 ng/mL·h) for the postprandial dose than for the fasting dose (P<0.05). All reported adverse effects were mild to moderate in intensity, and most (study 1) or all (study 2) occurred during the fasting state.
When administered with food, the bioavailability (AUC and Cmax) of gepirone ER was greater than during the fasting state, with the greatest bioavailability seen when the drug was taken 15 minutes after eating. Based on this pharmacokinetic analysis, it may be prudent to administer gepirone ER consistently, either always with or always without food.
新型抗抑郁药吉哌隆优先作用于5-羟色胺1A（5-HT1A）受体，作为5-HT1A激动剂发挥作用。安慰剂对照临床研究已证实吉哌隆具有良好的安全性，对抑郁症治疗有效。此前一项研究表明，餐后15分钟而非空腹时服用速释吉哌隆，可使血浆浓度-时间曲线下平均面积（AUC）增加37%。吉哌隆被重新制成缓释（ER）剂型，这就需要进一步探究食物对其生物利用度的影响。
本文描述了2项关于吉哌隆ER及其1种代谢物1-(2-嘧啶基)-哌嗪（1-PP）在健康受试者体内药代动力学特性的研究。在研究1中，我们评估了食物以及进食时间相对于给药时间对吉哌隆ER生物利用度的影响。研究2的目的是确认吉哌隆ER在进食和空腹条件下具有相似的药代动力学特征。
开展了2项开放标签、随机、单剂量、交叉研究，对一级残留效应进行了平衡，以评估ER片剂中吉哌隆的生物利用度。健康男性受试者口服20 mg吉哌隆ER。在研究1中，受试者在禁食10小时后或在标准高脂餐后1小时、15分钟或2小时服用吉哌隆ER剂量。在研究2中，受试者要么在禁食10小时后服用吉哌隆ER剂量，并继续禁食4小时，要么在标准高脂餐后15分钟服用吉哌隆ER剂量。
28名男性（平均[标准差]年龄，27.2[6.6]岁）参与了研究1，27名男性（平均[标准差]年龄，31.8[9.6]岁）参与了研究2。在研究1中，吉哌隆ER的平均（标准差）最大血浆峰浓度（Cmax）餐后15分钟给药组比空腹给药组高69.2%（3.25[1.71]对1.92[0.96]ng/mL）（P≤0.05），0至30小时的AUC餐后15分钟给药组比空腹给药组高31.9%（39.3[20.6]对29.8[15.3]ng/mL·h）（P≤0.05）。在研究2中，吉哌隆的平均Cmax餐后给药组比空腹给药组高62.0%（4.13对2.55 ng/mL），0至无穷大的平均AUC餐后给药组比空腹给药组高24%（38.71对31.14 ng/mL·h）（P<0.05）。所有报告的不良反应强度均为轻度至中度，且大多数（研究1）或全部（研究2）发生在空腹状态。
与食物一起服用时，吉哌隆ER的生物利用度（AUC和Cmax）高于空腹状态，进食后15分钟服用该药时生物利用度最高。基于此药代动力学分析，始终与食物一起或始终不与食物一起服用吉哌隆ER可能更为谨慎。
